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分子细胞生物学报（英文版）

分子细胞生物学报（英文版）

Journal of Molecular Cell Biology
本刊为专业学术性刊物。主要刊载有关实验生物学、动植物细胞生物学、发育生物学、生殖生物学、肿瘤生物学和免疫生物学等方面的创造性论文、简报及特约综述，反映本学科的最新研究成果。读者对象为与本学科有关的大专院校师生及医学、生物学的科研人员。
  • 发文量：1389
  • 被引量：370
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  • 国内刊号/CN：31-1976/Q
    国际刊号/ISSN：1673-520X
  • 发行周期：双月刊
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  • 主管单位：中国科学院
    主办单位：中国科学院上海生命科学研究院；生物化学与细胞生物学研究所；中国细胞生物学学会
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  • 主编：徐永华
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  • 邮箱：jmcb@sibs.ac.cn，edto@sunm.shcnc.ac.cn,
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分子细胞生物学报（英文版） >2023年第1期

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  • 摘要：Mdm2 and Mdm4 are negative regulators of the tumour suppressor p53;hence,this relationship is the focus of many cancerrelated studies.A multitude of experiments across various developmental stages have been conducted to explore the tissuespecific rotes of these proteins in the mouse.When Mdm2 or Mdm4 are deleted in the germline or specific tissues,they display different phenotypic defects,some of which lead to embryonic lethality.Mdm2 loss is often more deleterious than loss of its homologue Mdm4.All tissues experience activation of p53 target genes upon loss of Mdm2 or Mdm4;however,the degree towhich the p53 pathway is perturbed is highly tissue-specific and does not correlate to the severity of the morphological phenotypes.Therefore,a need for further understanding of how these proteins regulate p53 activity is warranted,as therapeutic targeting of the p53 pathway is rapidly evolving and gaining attention in the field of cancer research.In this review,we discuss the tissue-specificity of Mdm proteins in regulating p53 and expose the need for investigation at the cell-specific level.
  • 摘要：The transcriptional factor p53 activates the expression of a myriad of target genes involving a complicated signalling network,resulting in various cellular outcomes,such as growth arrest,senescence,apoptosis,and metabolic changes,and leading to consequent suppression of tumour growth and progression.Because of the profoundly adverse effect of p53 on growth and prolifer ation of cancer cells,several feedback mechanisms have been employed by the cells to constrain p53 activity.Two major antagonists MDM2 and MDMX (the long forms) are transcriptionally induced by p53,but in return block p53 activity,forming a negative feedback circuit and rendering chemoresistance of several cancer cells.However,they are not alone,as cancer cells also employ other proteins encoded by p53 target genes to inhibit p53 activity at transcriptional,translational,and posttranslational levels.This essay is thus composed to review a recent progress in understanding the mechanisms for how cancer cells hijack the p53 autoregulation by these proteins for their growth advantage and to discuss the clinical implications of these autoregulatory loops.
  • 摘要：Mouse double minute (Mdm) genes span an evolutionary timeframe from the ancient eukaryotic placozoa Trichoplax adhaerens to Homo sapiens,implying a significant and possibly conserved cellular role throughout history.Maintenance of DNA integrity and response to DNA damage involve many key regulatory pathways,including precise control over the tumour suppressor protein p53.In most vertebrates,degradation of p53 through proteasomal targeting is primarily mediated by heterodimers of Mdm2 and the Mdm2-related protein Mdm4 (also known as MdmX).Both Mdm2 and Mdm4 have p53-binding regions,acidic domains,zinc fingers,and C-terminal RING domains that are conserved throughout evolution.Vertebrates typically have both Mdm2 and Mdm4genes,while analyses of sequenced genomes of invertebrate species have identified single Mdm genes,suggesting that a duplication event occurred prior to emergence of jawless vertebrates about 550-440 million years ago.The functional relationship between Mdm and p53 in T.adhaerens,an organism that has existed for 1 billion years,implies that these two proteins have evolved together to maintain a conserved and regulated function.
  • 摘要：The major cause of death from breast cancer is not the primary tumour,but relapsing,drug-resistant,metastatic disease.Identifying factors that contribute to aggressive cancer offers important leads for therapy.Inherent defence against carcinogens depends on the individual molecular make-up of each person.Important molecular determinants of these responses are under the control of the mouse double minute (MDM) family:comprised of the proteins MDM2 and MDM4.In normal,healthy adult cells,the MDM family functions to critically regulate measured,cellular responses to stress and subsequent recovery.Proper function of the MDM family is vital for normal breast development,but also for preserving genomic fidelity.The MDM family members are best characterized for their negative regulation of the major tumour suppressor p53 to modulate stress responses.Their impact on other cellular regulators is emerging.Inappropriately elevated protein levels of the MDM family are highly associated with an increased risk of cancer incidence.Exploration of the MDM family members as cancer therapeutic targets is relevant for designing tailored anti-cancer treatments,but successful approaches must strategically consider the impact on both the target cancer and adjacent healthy cells and tissues.This review focuses on recent findings pertaining to the role of the MDM family in normal and malignant breast cells.
  • 摘要：It is well established that both p53 and MDM2 are short-lived proteins whose stabilities are tightly controlled through ubiquitination-mediated degradation.Although numerous studies indicate that the MDM2 E3 ligase activity,as well as the protein-protein interaction between p53 and MDM2,is the major focus for this regulation,emerging evidence suggests that the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP,also known as USP7) plays a critical role.Furthermore,HAUSP inhibition elevates p53 stability and might be beneficial for therapeutic purposes.In this review,we discuss the advances of this dynamic pathway and the contributions of positive and negative regulators affecting HAUSP activity.We also highlight the roles of HAUSP in cancer justifying the production of the first generation of HAUSP inhibitors.
  • 摘要：Neuropathic pain is a debilitating clinical condition with few efficacious treatments,warranting development of novel therapeutics.Ozone is widely used as an alternative therapy for many different pain conditions,with exact mechanisms still elusive.In this study,we found that a single peri-sciatic nerve injection of ozone decreased mechanical allodynia and thermal hyperalgesia,and normalized the phosphorylation of protein kinase C γ,N-methyl-D-aspartate receptor,and extracellular signal-regulated kinase in a chronic constriction injury (CCl) model in rat sciatic nerve.Meanwhile,ozone significantly suppressed CCI-induced activation of spinal microglia.More importantly,the anti-nociceptive effect of ozone depended on the activation of 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK),which was proved by the fact that the phosphorylated AMPK level increased during the ozone therapy and AMPK antagonist abolished the effect of ozone in vivo and in vitro.In addition,direct injection of AMPK agunist could replicate the anti-nociceptive effect of ozone in CCl rats.In conclusion,our observations indicate that peri-sciatic nerve injection of ozone activates AMPK to attenuate CCl-induced neuropathic pain.
  • 摘要：Homoeostatic regulation of the light sensor,rhodopsin,is critical for the maintenance of light sensitivity and survival of photoreceptors.The major fly rhodopsin,Rh1,undergoes light-induced endocytosis and degradation,but its protein and mRNA levels remain constant during light/dark cycles.It is not clear how translation of Rh1 is regulated.Here,we show that adult photoreceptors maintain a constant,abundant quantity of ninoE mRNA,which encodes Rh1.We demonstrate that the Fmr1 protein associates with ninoE mRNA and represses its translation.Further,light exposure triggers a calcium-dependent dephosphorylation of Fmr1,which relieves suppression of Rh1 translation.We demonstrate that Mts,the catalytic subunit of protein phosphatase 2A (PP2A),mediates light-induced Fmr1 dephosphorylation in a regulatory B subunit of PP2A (CKa)-dependent manner.Finally,we show that blocking light-induced Rh1 translation results in reduced light sensitivity.Our results reveal the molecular mechanism of Rh1 homoeostasis and physiological consequence of Rh1 dysregulation.
  • 摘要：Dystrobrevin-binding protein 1 (Dtnbp1) is one of the earliest identified schizophrenia susceptibility genes.Reduced expression of DTNBP1 is commonly found in brain areas of schizophrenic patients.Dtnbp1-null mutant mice exhibit abnormalities in behaviors and impairments in neuronal activities.However,how diminished DTNBP1 expression contributes to clinical relevant features of schizophrenia remains to be illustrated.Here,using a conditional Dtnbp1 knockout mouse line,we identified an in vivo schizophrenia-relevant function of DTNBP1 in pyramidal neurons of the medial prefrontal cortex (mPFC).We demonstrated that DTNBP1 elimination specifically in pyramidal neurons of the mPFC impaired mouse pre-pulse inhibition (PPI) behavior and reduced perisomatic GABAergic synapses.We further revealed that loss of DTNBP1 in pyramidal neurons diminished activitydependent secretion of brain-derived neurotrophic factor (BDNF).Finally,we showed that chronic BDNF infusion in the mPFC fully rescued both GABAergic synaptic dysfunction and PPI behavioral deficit induced by DTNBP1 elimination from pyramidal neurons.Our findings highlight brain region-and cell type-specific functions of DTNBP1 in the pathogenesis of schizophrenia,and underscore BDNF restoration as a potential therapeutic stratesy for schizophrenia.
  • 摘要：Deregulation of the tyrosine kinase signalling is often associated with tumour progression and drug resistance,but its underlying mechanisms are only partly understood.In this study,we investigated the effects of the receptor tyrosine kinase AXL on the stability of the MDMX-MDM2 heterocomplex and the activity of p53 in melanoma cells.Our data demonstrated that AXL overexpression or activation through growth arrest-specific 6 (Gas6) ligand stimulation increases MDMX and MDM2 protein levels and decreases p53 activity.Upon activation,AXL stabilizes MDMX through a post-translational modification that involves phosphorylation of MDMX on the phosphosite Ser314,leading to increased affinity between MDMX and MDM2 and favouring MDMX nuclear transiocation.Ser314 phosphorylation can also protect MDMX from MDM2-mediated degradation,leading to stabilization of the MDMX-MDM2 complex.We identified CDK4/6 and p38 MAPK as the two kinases mediating AXL-induced modulation of the MDMX-MDM2 complex,and demonstrated that suppression of AXL,either through siRNA silencing or pharmacological inhibition,increases expression levels of p53 target genes P21,MDM2,and PUMA,improves p53 pathway response to chemotherapy,and sensitizes cells to both Cisplatin and Vemurafenib.Our findings offer an insight into a novel signalling axis linking AXL to p53 and provide a potentially drugguble pathway to restore p53 function in melanoma.
  • 摘要：Subcellular localization and translation of messenger RNAs are essential for the regulation of neuronal development and synaptic function.As post-transcriptional regulators,microRNAs (miRNAs) have been emerging as central players in the development and maturation of the nervous system.Recent discoveries reveal the critical functions of miRNAs in the axon of neurons via multiple pathways of molecular regulation.Here,we introduce methods for isolating axonal miRNAs and review recent findings on the localization and function as well as regulatory mechanism of axonal miRNAs during axon development.
  • 摘要：The endocannabinoid system (ECS) is a key cellular signalling system that has been implicated in the resulation of diverse cellular functions.Importantly,growing evidence suggests that the biological actions of the ECS may,in part,be mediated through its ability to regulate the production and/or release of nitric oxide,a ubiquitous bioactive molecule,which functions as a versatile signalling intermediate.Herein,we review and discuss evidence pertaining to ECS-mediated regulation of nitric oxide production,as well as the involvement of reactive nitrogen species in resulating ECS-induced signal transduction by highlighting emerging work supporting nitrergic modulation of ECS function.Importantly,the studies outlined reveal that interactions between the ECS and nitrergic signalling systems can be both stimulatory and inhibitory in nature,depending on cellular context.Moreover,such crosstalk may act to maintain proper cell function,whereas abnormalities in either system can undermine cellular homoeostasis and contribute to various pathologies associated with their dysresulation.Consequently,future studies targeting these signalling systems may provide new insights into the potential role of the ECS-nitfic oxide signalling axis in disease development and/or lead to the identification of novel therapeutic targets for the treatment of nitrosative stress-related neurological,cardiovascular,and metabolic disorders.
  • 摘要：Interferon-γ (IFN-γ) triggers macrophage for inflammation response by activating the intracellular JAK-STAT1 signaling.Suppressor of cytokine signaling 1 (SOCS1) and protein tyrosine phosphatases can negatively modulate IFN-γ signaling.Here,we identify a novel negative feedback loop mediated by STAT3-SOCS3,which is tightly controlled by SENP1 via de-SUMOylation of protein tyrosine phosphatase 1B (PTP1B),in IFN-γ signaling.SENP1-deficient macrophages show defects in IFN-γ signaling and M1 macrophage activation.PTP1B in SENP1-deficient macrophages is highly SUMOylated,which reduces PTP1B-induced de-phosphorylation of STAT3.Activated STAT3 then suppresses STAT1 activation via SOCS3 induction in SENP1-deficient macrophages.Accordingly,SENP1-deficient macrophages show reduced ability to resist Listeria monocytogenes infection.These results reveal a crucial role of SENP1-controlled STAT1 and STAT3 balance in macrophage polarization.
  • 摘要：Small nucleolar RNA (snoRNA) dysfunctions have been associated with cancer development.SNORD126 is an orphan C/D box snoRNA that is encoded within introns 5-6 of its host gene,cyclin B1-interacting protein 1 (CCNB1lP1).The cancer-associated molecular mechanisms triggered by SNORD126 are not fully understood.Here,we demonstrate that SNORD126 is highly expressed in hepatocellular carcinoma (HCC) and colorectal cancer (CRC) patient samples.SNORD126 increased Huh-7 and SW480 cell growth and tumorigenicity in nude mice.Knockdown of SNORD126 inhibited HepG2 and LS174T cell growth.We verified that SNORD126 was not processed into small RNAs with miRNA activity.Moreover,SNORD126 did not show a significant expression correlation with CCNB1lP1 in HCC samples or regulate CCNB1lP1 expression.Our gene expression profile analysis indicated thatSNORD126-upregulated genes frequently mapped to the PI3K-AKT pathway.SNORD126 overexpression increased the levels of phosphorylated AKT,GSK-3β,and p70S6K and elevated fibroblast growth factor receptor 2 (FGFR2) expression.siRNA-mediated knockdown or AZD4547-mediated inactivation of FGFR2 in SNORD126-overexpressing Huh-7 cells inhibited AKT phosphorylation and suppressed cell growth.These findings indicate an oncogenic role for SNORD126 in cancer and suggest its potential as a therapeutic target.
  • 摘要：Neuroligins (Nlgs) are transmembrane cell adhesion molecules playing essential roles in synapse development and function.Genetic mutations in neuroligin genes have been linked with some neurodevelopmental disorders such as autism.These mutated Nlgs are mostly retained in the endoplasmic reticulum (ER).However,the mechanisms underlying normal Nlg maturation and trafficking have remained largely unknown.Here,we found that Drosophila neuroligin 2 (DNlg2) undergoes proteolytic cleavage in the ER in a variety of Drosophila tissues throughout developmental stages.A region encompassing Y642-T698 is required for this process.The immature non-cleavable DNlg2 is retained in the ER and non-functional.The C-terminal fragment of DNlg2 instead of the full-length or non-cleavable DNlg2 is able to rescue neuromuscular junction defects and GluRIIB reduction induced by dnlg2 deletion.Intriguingly,the autism-associated R598C mutation in DNlg2 leads to similar marked defects in DNlg2 proteolytic process and ER export,revealing a potential role of the improper Nlg cleavage in autism pathogenesis.Collectively,our findings uncover a specific mechanism that controls DNlg2 maturation and trafficking via proteolytic cleavage in the ER,suggesting that the perturbed proteolytic cleavage of Nlgs likely contributes to autism disorder.
  • 摘要：The co-translational targeting or insertion of secretory and membrane proteins into the endoplasmic reticulum (ER) is a key biological process mediated by the signal recognition particle (SRP).In eukaryotes,the SRP68-SRP72 (SRP68/72) heterodimer plays an essential role in protein translocation.However,structural information on the two largest SRP proteins,SRP68 and SRP72,is limited,especially regarding their interaction.Herein,we report the first crystal structures of human apo-SRP72 and the SRP68/72 complex at 2.91 A and 1.7 A resolution,respectively.The SRP68-binding domain of SRP72 contains four atypical tetratricopeptide repeats (TPR) and a flexible C-terminal cap.Apo-SRP72 exists mainly as dimers in solution.To bind to SRP68,the SRP72 homodimer disassociates,and the indispensable C-terminal cap undergoes a pronounced conformational change to assist formation of the SRP68/72 heterodimer.A 23-residue polypeptide of SRP68 is sufficient for tight binding to SRP72 through its unusually hydrophobic and extended surface.Structural,biophysical,and mutagenesis analyses revealed that cancer-associated mutations disrupt the SRP68-SRP72 interaction and their co-localization with ER in mammalian cells.The results highlight the essential role of the SRP68-SRP72 interaction in SRP-mediated protein translocation and provide a structural basis for disease diagnosis,pethophysiology,and drug design.
  • 摘要：Faithful transmission or restoration of epigenetic information such as repressive histone modifications through generations is critical for the maintenance of cell identity.We report here that chromodomain Y-like protein (CDYL),a chromodomain-containing transcription corepressor,is physically associated with chromatin assembly factor 1 (CAF-1) and the replicative helicase MCM complex.We showed that CDYL bridges CAF-1 and MCM,facilitating histone transfer and deposition during DNA replication.We demonstrated that CDYL recruits histone-modifying enzymes G9a,SETDB1,and EZH2 to replication forks,leading to the addition of H3K9me2/3 and H3K27me2/3 on newly deposited histone H3.Significantly,depletion of CDYL impedes early S phase progression and sensitizes cells to DNA damage.Our data indicate that CDYL plays an important role in the transmission/restoration of repressive histone marks,thereby preserving the epigenetic landscape for the maintenance of cell identity.
  • 摘要：Extraribosomal functions of ribosomal proteins (RPs) have gained much attention for their implications in tumorigenesis and progression.However,the regulations for transition between the ribosomal and extraribosomal functions of RPs are rarely reported.Herein,we identified a ribosomal protein S7-interacting partner,BCCIPβ,which modulates the functional conversion of S7.Through the N-terminal acidic domain,BCClPβ interacts with the central basic region in S7 and regulates the extraribosomal distribution of S7.BCCIPβ deficiency abrogates the ribosomal accumulation but enhances the ribosome-free location of S7.This translocation further impairs protein synthesis and triggers ribosomal stress.Consequently,BCClPβ deficiency suppresses the ribosomal function and initiates the extraribosomal function of S7,resulting in restriction of cell proliferation.Moreover,clinically relevant S7 mutations were found to dampen the interaction with BCCIPβ and facilitate the functional transition of S7.In conclusion,BCCIPβ,as a S7 modulator,contributes to the regulation of ribosomal and extraribosomal functions of S7 and has implications in cell growth and tumor development.
  • 摘要：Most E26 transformation-specific (ETS) transcription factors are involved in the pathogenesis and progression of cancer.This is in part due to the roles of ETS transcription factors in basic biological processes such as growth,proliferation,and differentiation,and also because of their regulatory functions that have physiological relevance in tumorigenesis,immunity,and basal cellular homoeostasis.A member of the E74-like factor (ELF) subfamily of the ETS transcription factor family-myeloid elf-1-like factor (MEF),designated as ELF4-has been shown to be critically involved in immune response and signalling,osteogenesis,adipogenesis,cancer,and stem cell quiescence.ELF4 carries out these functions as a transcriptional activator or through interactions with its partner proteins.Mutations in ELF4 cause aberrant interactions and induce downstream processes that may lead to diseased cells.Knowing how ELF4 impinges on certain cellular processes and how it is regulated in the cells can lead to a better understanding of the physiological and pathological consequences of modulated ELF4 activity.
  • 摘要：Farnesoid X receptor (FXR) is a ligand-activated nuclear receptor that plays a central role in regulating genes involved in bile acid homeostasis,and fat and glucose metabolism.Here,we demonstrate a post-translational interplay between FXR phosphorylation,SUMOylation,and ubiquitination that directs the receptor into an activation-degradation pathway in hepatocytes.We identify a non-canonical SUMOylation motif termed pSuM that conjugates SUMO2 at Lys-325 of FXR under the direct control of casein kinase 2 (CK2),which provides the required negative charge for Ubc9 and PIAS1 to perform SUMOylation,by phosphorylating Ser-327.Lys-325 SUMOylation is indispensable to the promotion of efficient ligand activation and transcriptional coactivation of FXR.Constitutive pSuM activation using a phospho-mimic Ser-327 mutant or catalytic CK2 expression strongly induces SUMO2 conjugation,which directs FXR ubiquitination and proteasome-dependent degradation.We also determine that such SUMOylation-dependent ubiquitination of FXR is mediated by the E3 ubiquitin ligase RNF4,which is required to achieve maximal induction of FXR and optimal up-or downregulation of responsive genes involved in bile acid homeostasis and liver regeneration.Our findings identify a highly regulated atypical SUMO conjugation motif that serves to coordinate FXR transcriptional competence,thereby expanding the intricate dynamics of the SUMOylation process used by incoming signals to govern metabolic gene regulation.
  • 摘要：Ca2+ signals participate in various cellular processes with spatial and temporal dynamics,among which,inositol 1,4,5-tdsphosphate receptors (IP3Rs)-mediated Ca2+ signals are essential for early development.However,the underlying mechanisms of IP3R-regulated cell fate decision remain largely unknown.Here we report that IP3Rs are required for the hematopoietic and cardiac fate divergence of mouse embryonic stem cells (mESCs).Deletion of IP3Rs (IP3R-tKO) reduced Flk1+/PDGFRα-hematopoietic mesoderm,c-Kit+/CD41+ hematopoietic progenitor cell population,and the colony-forming unit activity,but increased cardiac progenitor markers as well as cardiomyocytes.Concomitantly,the expression of a key regulator of hematopoiesis,Etv2,was reduced in IP3R-tKO cells,which could be rescued by the activation of Ca2+ signals and calcineudn or overexpression of constitutively active form of NFATc3.Furthermore,IP3R-tKO impaired specific targeting of Etv2 by NFATc3 via its evolutionarily consewed cis-element in differentiating ESCs.Importantly,the activation of Ca2+-calcineurin-NFAT pathway reversed the phenotype of IP3R-tKO cells.These findings reveal an unrecognized governing role of IP3Rs in hematopoletic and cardiac fate commitment via IP3Rs-Ca2+-calcineudn-NFATc3-Etv2 pathway.
  • 摘要：Mesenchymal stem cells (MSCs) have been demonstrated to have promising therapeutic benefits for a variety of neurological diseases;however,the underlying mechanisms are poorly understood.Here,we showed that intravitreal infusion of MSCs promoted retinal ganglion cell (RGC) survival in a mouse model of acute glaucoma,with significant inhibition of microglial activation,production of TNF-α,IL-1β,and reactive oxygen species,as well as caspase-8 and caspase-3 activation.In vitro,MSCs inhibited bothcaspase-8-mediated RGC apoptosis and microglial activation,partly via the action of stanniocalcin 1 (STC1).Furthermore,we found that microRNA-21a-5p (miR-21) and its target,PDCD4,were essential for STC1 production and the neuroprotective property of MSCs in vitro and in vivo.Importantly,miR-21 overexpression or PDCD4 knockdown augmented MSC-mediated neuroprotective effects on acute glaucoma.These data highlight a previously unrecognized neuroprotective mechanism by which the miR-21/PDCD4 axis induces MSCs to secrete STC1 and other factors that exert neuroprotective effects.Therefore,modulating the miR-21/PDCD4 axis might be a promising strategy for clinical treatment of acute glaucoma and other neurological diseases.
  • 摘要：Glioblastoma multiforme (GBM) is a highly invasive brain tumor with limited therapeutic means and poor prognosis.Recent studies indicate that glioma-initiating cells/glioma stem cells (GICs/GSCs) may be responsible for tumor initiation,infiltration,and recurrence.GlCs could aberrantly employ molecular machinery balancing self-renewal and differentiation of embryonic neural precursors.Here,we find that paired related homeobox 1 (PRRX1),a homeodomain transcription factor that was previously reported to control skeletal development,is expressed in cortical neural progenitors and is required for their self-renewal and proper differentiation.Further,PRRX1 is overrepresented in glioma samples and labels GlCs.Glioma cells and GlCs depleted with PRRX1 could not propagate in vitro or form tumors in the xenograft mouse model.The GIC self-renewal function regulated by PRRX1 is mediated by dopamine D2 receptor (DRD2).PRRX1 directly binds to the DRD2 promoter and transactivates its expression in GlCs.Blockage of the DRD2 signaling hampers GIC self-renewal,whereas its overexpression restores the propagating and tumorigenic potential of PRRX1-depleted GlCs.Finally,PRRX1 potentiates GlCs via DRD2-mediated extracellular signal-related kinase (ERK) and AKT activation.Thus,our study suggests that therapeutic targeting the PRRX1-DRD2-ERK/AKT axis in GlCs is a promising strategy for treating GBMs.
  • 摘要：Meningiomas are the most common primary tumors in central nervous system.While recent studies have revealed genetic clues to lower grade human meningiomas,the molecular determinants driving the progression and recurrence of anaplastic meningioma,the most malignant subtype with a low prevalence but high morbidity,are still poorly understood.It has been proposed that high recurrence rates of malignant meningiomas are linked to cancer stem cells.Indeed,tumor stem-like cells have been isolated from various meningioma subtypes,but never been obtained from anaplastic meningioma.In this study,we successfully isolated stem-like cells from human anaplastic meningioma.These cells are capable of forming spheres and initiating xenograft tumors that recapitulate anaplastic meningioma phenotypes,and thus could serve as an in vitro model for malignant meningiomas.KLF4,a transcription factor known for its role in stemness maintenance,was identified as one of the most frequently mutated genes in the benign secretory meningioma.Interestingly,we found that KLF4 is downregulated in anaplastic meningioma compared with low-grade meningioma subtypes.By manipulating KLF4 expression in anaplastic meningioma stem-like cells,we demonstrated that KLF4 acts as a tumor suppressor during malignant progression in meningioma,affecting apoptosis,proliferation,invasion,and cell cycle.These results suggest a potential therapeutic value of KLF4 for clinical intervention of anaplastic meningioma.
  • 摘要：Retinoic acid (RA),a bioactive metabolite of vitamin A,is a critical mediator of cell differentiation.RA blocks adipogenesis,but mechanisms remain to be established.ZFP423 is a key transcription factor maintaining white adipose identity.We found that RA inhibits Zfp423 expression and adipogenesis via blocking DNA demethyiation in the promoter of Zfp423,a process mediated by growth arrest and DNA-damage-inducible protein alpha (GADD45A).RA induces the partnering between retinoic acid receptor (RAR) and tumor suppressor inhibitor of growth protein 1 (ING1),which prevents the formation of GADD45A and ING1 complex necessary for locus-specific Zfp423 DNA demethylation.In vivo,vitamin A supplementation prevents obesity,downregulates Gadd45a expression,and reduces GADD45A binding and DNA demethylation in the Zfp423 promoter.Inhibition of Zfp423 expression due to RA contributes to the enhanced brown adipogenesis.In summary,RA inhibits white adipogenesis by inducing RAR and ING1 interaction and inhibiting Gadd45a expression,which prevents GADD45A-mediated DNA demethylation.

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